Leukotriene receptor antagonist as a novel tocolytic in an in vitro model of human uterine contractility

Abstract

ObjectiveThis study analyzed the ability of montelukast, a cysteinyl-leukotrienes receptor antagonist and anti-inflammatory agent, to produce a consistent tocolytic effect alone or in combination with nifedipine, a calcium (Ca2+) channel blocker currently used in clinical practice. Study designUterine biopsies were obtained from consenting women undergoing elective cesarean sections at term (n=20). Myometrial microsomal fractions were analyzed by immunoblotting to quantify relative cysteinyl leukotrienes receptor 1 (CysLTR1) levels. Isometric tension measurements were performed in vitro on human myometrial strips (n=120) in isolated organ baths in order to establish concentration–response curves to montelukast and to quantify changes in Ca2+ sensitivity on β-escin permeabilized tissues. ResultsImmunodetection analysis revealed the presence of CysLTR1 receptor in uterine tissues, fetal membranes and placenta. A significant increase in area under the curve (AUC) was quantified following the addition of leukotriene D4 (LTD4) (0.01–0.3μM), an end-product of the lipoxygenase pathway. Conversely, addition of montelukast produced a significant tocolytic effect by decreasing the frequency and AUC (IC50=1μM). Moreover, addition of montelukast also resulted in a reduced Ca2+ sensitivity as compared to control tissues (EC50 values of 654 and 403nM; p=0.02 at pCa 6), while an additive effect was observed in combination with 0.1nM nifedipine (p=0.004). ConclusionThis original study demonstrates the potency of montelukast as a tocolytic agent in an in vitro human uterine model. Montelukast, in combination with nifedipine, could represent a therapeutic approach to reduce inflammation associated with prematurity while facilitating the inhibition of preterm labor.